Chronic kidney disease (CKD) affects up to 26 million Americans, or 13% of the United States population. Moderate-severe CKD (stage 3-4, defined by glomerular filtration rate 15-59 mL/min/1.73m2) has a particularly large public health impact because it is most prevalent and because it potently amplifies risk of cardiovascular disease. Specifically, individuals with moderate-severe CKD have important "non-traditional" risk factors for cardiovascular disease which are not adequately addressed by risk reduction strategies developed for the general population. Insulin resistance is one "non-traditional" mechanism through which CKD may cause cardiovascular disease. In CKD, post-receptor resistance to insulin action in skeletal muscle is commonly acquired due to unique metabolic abnormalities, including impaired renal calcitriol synthesis, metabolic acidosis, and accumulation of uremic toxins. In turn, insulin resistance may promote cardiovascular disease by impairing endothelial function, increasing reactive oxygen species, and exacerbating systemic inflammation. The metabolic abnormalities unique to CKD fundamentally alter the pathophysiology and ascertainment of insulin resistance and offer novel potential targets for therapeutic intervention. The overall goal of this grant application is to comprehensively characterize insulin resistance in moderate- severe CKD. First, we propose to define the severity of insulin resistance, the compensatory response of the pancreatic beta cell, and net effects on glucose tolerance, which are currently poorly understood, using gold standard methods (hyperinsulinemic euglycemic clamp, intravenous glucose tolerance test, oral glucose tolerance test). Second, we propose to develop and validate formulae estimating insulin resistance for use in future epidemiologic studies and clinical trials. Third, we propose to test associations of insulin resistance with endothelial function, oxidative stress, and inflammation. To accomplish these goals, we have assembled a multidisciplinary team with expertise in the biology of CKD, metabolism, quantitative assessment of insulin sensitivity and beta-cell function, nutrition, and biostatistics. As part of this innovative collaborative approach, this study will take advantage of existing resources at the University of Washington and the Kidney Research Institute in Seattle. These include the Institute for Translational Health Sciences Clinical Research Center, Nutrition and Body Composition Core, and Center for Biomedical Statistics. PUBLIC HEALTH RELEVANCE: Moderate-severe CKD is an important public health problem due to its high prevalence and poor health outcomes. The key to improving long-term health outcomes in this population is prevention of cardiovascular disease. Persons with stage moderate-severe CKD are at high risk of cardiovascular events and are up to 11 times more likely to die, mostly due to cardiovascular disease, than to progress to kidney failure. Once completed, the proposed studies will provide a sound empirical basis to support the design of future large epidemiologic studies and clinical trials targeting insulin resistance in CKD. The ultimate goal of this work is to reduce the high morbidity and mortality in the large group of patients with moderate-severe CKD.